Palmitoyl Carnitine-Anchored Nanoliposomes for Neovasculature-Specific Delivery of Gemcitabine Elaidate to Treat Pancreatic Cancer

SIMPLE SUMMARY: Despite the availability of numerous therapeutic approaches, pancreatic ductal adenocarcinoma still stands as one of the most fatal cancers worldwide. Nanoliposomes could potentially be helpful in improving the pharmacokinetic and anticancer efficacy of drug molecules. Gemcitabine is the first line of therapy, but due to its hydrophilic nature, entrapment within nanoliposomes is very limited. To overcome this problem, we explored the lipophilic form of gemcitabine, i.e., Gemcitabine Elaidate. The present study is aimed towards investigating the antitumor activity of Gemcitabine Elaidate and further designing an appropriate nano-liposomal formulation in combination with Palmitoyl-DL-carnitine chloride as a Protein kinase C (PKC) inhibitor. Our combination therapy in a nano-liposomal carrier resulted in enhanced cellular uptake, inhibition of angiogenesis potential and augmented anticancer potency in both 2D and 3D in vitro models of pancreatic tumors. The promising results indicate the successful development of a nano-liposomal carrier incorporating Gemcitabine Elaidate and Palmitoyl-DL-carnitine chloride as a more effective approach for the treatment of pancreatic cancer by overcoming the key drawbacks of the current first-line therapy. ABSTRACT: Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC.